Buprenorphine-wafer for drug substitution therapy

ABSTRACT

The present invention relates to oral pharmaceutical dosage forms comprising buprenorphine with the dosage form releasing buprenorphine instantly upon oral, preferably sublingual, application of the dosage form. The present invention also relates to the use of such dosage forms for treating pain in a human or animal or for drug substitution therapy in drug-dependent human subjects.

The present invention relates to oral pharmaceutical dosage formscomprising buprenorphine with the dosage form releasing buprenorphineinstantly upon oral, preferably sublingual, application of the dosageform. The present invention also relates to the use of such dosage formsfor treating pain in a human or animal or for drug substitution therapyin drug-dependent human subjects.

BACKGROUND OF THE INVENTION

Chronic pain, which may be due to idiopathic reasons, cancer or otherdiseases such as rheumatism and arthritis, is typically treated withstrong opioids.

Over the last decades prejudices in the medical community as to the useof strong opioids for treating chronic pain in patients hassignificantly decreased. Many of the se prejudices were due to some ofthe characteristics being inherent to opioids.

While opioids have always been known to be useful in pain treatment,they also display an addictive potential in view of their euphorigenicactivity. Thus, if opioids are taken by healthy human subjects with adrug seeking behaviour they may lead to psychological as well asphysical dependence.

These usually undesired characteristics of opioids can however becomeimportant in certain scenarios such as drug substitution therapies fordrug addicts. One of the fundamental problems of illicit drug abuse bydrug addicts (“junkies”) who are dependent on the constant intake ofillegal drugs such as heroin is the drug-related criminal activitiesresorted to by such addicts in order to raise enough money to fund theiraddiction. The constant pressures upon addicts to procure money forbuying drugs and the concomitant criminal activities have beenincreasingly recognised as a major factor that counteracts efficient andlong-lasting withdrawal and abstinence from drugs.

Therefore, programmes have been developed, particularly in the UnitedStates and western European countries, in which drug addicts are allowedto take prescription drugs under close supervision of medicalpractitioners instead of illegal drugs such as street heroin.

The aim of drug substitution theory is thus to first enable addicts tolead a regular life by administering legal drugs to prevent withdrawalsymptoms, but because of their legal character and prescription bymedical practitioners do not lead to the aforementioned describeddrug-related criminal activities. In a second and/or alternate step inthe treatment of drug addiction may be to slowly make the drug addictless dependent on the drug by gradually reducing the dose of thesubstitution drug or to bridge the time until a therapy place in awithdrawal programme is available.

The standard drug used in drug substitution therapy programmes has for along time been methadone. However, in recent years the potential ofother opioids as substitution drugs in substitution therapy has beenrecognised. A particularly suitable drug for that purpose is the opioidbuprenorphine, which is a mixed opioid agonist/antagonist.

Nowadays, buprenorphine preparations are administered in drugsubstitution programmes in the form of a tablet for sublingualadministration. One of the reasons that the tablets are formulated forsublingual administration is that this the preferred route ofadministration for buprenorphine. Furthermore, if a patient swallowssuch tablets they will not provide euphorigenic activity.

One example of sublingual tablets for drug substitution therapy is thepreparation Subutex® (being marketed in Germany by Essex Pharma).

Nevertheless, drug addicts sometimes still try to divert thesesublingual buprenorphine tablets by removing them from the mouth whenthe supervising healthcare professional's attention is directed to otheractivities. Later the tablets may be sold or the active agentbuprenorphine isolated/extracted to apply it parenterally.

Another buprenorphine preparation aimed at preventing this potentialpossibility of abuse has recently gained administrative approval in theUnited States (Suboxone®). The Suboxone® preparation comprisesbuprenorphine hydrochloride and the opioid antagonist naloxonehydrochloride dihydrate. The presence of naloxone is intended to preventparenteral abuse of buprenorphine as parenteral co-administration ofbuprenorphine and naloxone in e.g. an opioid-dependent addict will leadto serious withdrawal symptoms.

However, there remains a need for other diversion and/or abuse-resistantdosage forms of buprenorphine, which can be used in drug substitutiontherapy as described above. Additionally, it would be desirable to havea buprenorphine preparation available which is diversion and/orabuse-resistant in cases where the preparation is used for drugsubstitution therapy and which could also provide efficient analgesia incases where the preparation is administered to alleviate pain in apatient.

OBJECT AND SUMMARY OF THE INVENTION

It is an object of the present invention to provide an oralpharmaceutical dosage form of the active agent buprenorphine that isless prone to diversion and/or abuse in drug substitution therapy. It isanother object of the present invention to provide an oral dosage formof the active agent buprenorphine that can be used for drug substitutiontherapy and/or pain treatment.

In one embodiment the present invention relates to an oralpharmaceutical dosage form comprising at least buprenorphine or apharmaceutically acceptable salt thereof with a dosage form releasingbuprenorphine or said pharmaceutically acceptable salt thereof instantlyupon or oral, preferably sublingual, application of the dosage form. Itis, however, understood that the invention and its various embodimentswhich are set out below, can be extended to any opioid or analgesicwhose preferred route of administration is oral, prefereably sublingual,as is the case for buprenorphine.

An instant release of buprenorphine or a pharmaceutically acceptablesalt thereof upon oral, preferably sublingual, application means thatsubstantially all of the buprenorphine or said pharmaceuticallyacceptable salt thereof will be released within less than three minutes,preferably within less than two minutes or less than one minute. Evenmore preferably, substantially all of the buprenorphine or saidpharmaceutically acceptable salt thereof will be released within lessthan thirty seconds, twenty seconds, ten seconds or even within lessthan five seconds after oral, preferably sublingual, application of thedosage form. In one of the preferred embodiments these oral dosage formswill comprise between approximately 0.1 mg and approximately 16 mgbuprenorphine or the equivalent amounts of a pharmaceutically acceptablesalt thereof.

In a further preferred embodiment these oral pharmaceutical dosage formswill achieve an average C_(max) of between 1.5 ng/ml and approximately2.25 ng/ml in the case of a dose of 0.4 mg buprenorphine hydrochloridebeing administered. In the case of a dose of 8 mg buprenorphine HClbeing administered, the C_(max) will typically be between approximately2.5 and 3.5 ng/ml and if a dose of 16 mg buprenorphine hydrochloride isadministered the C_(max) will preferably be between 5.5 to 6.5 ng/ml.

Yet another preferred embodiment of the invention relates to oralpharmaceutical dosage forms which may provide for the above-mentionedcharacteristics and/or an average Tmax of from approximately 45 toapproximately 90 minutes.

In a particularly preferred embodiment the dosage forms willadditionally comprise an opioid antagonist, preferably naloxone or apharmaceutically acceptable salt thereof.

In yet a further preferred embodiment, the pharmaceutical dosage formwill comprise buprenorphine and the opioid antagonist, which preferablyis naloxone, in a weight ratio of from approximately 1:1 toapproximately 10:1.

One embodiment of the present invention also relates to oralpharmaceutical dosage forms, which may have some or all of theaforementioned characteristics and wherein the dosage form has afilm-like or wafer-like shape.

Another embodiment relates to a method of manufacturing theafore-mentioned described dosage forms.

Embodiments of the present invention also relate to the use of theafore-described oral, preferably sublingual, pharmaceutical dosage formsin the manufacture of a medicament for treating pain in a human oranimal and/or for drug substitution therapy in drug-dependent humansubjects.

One aspect of the invention also relates to a method of drugsubstitution therapy in drug-dependent human subjects wherein theaforementioned oral pharmaceutical dosage forms are administered to adrug-dependent subject in need thereof.

DETAILED DESCRIPTION OF THE INVENTION

From the prior art, sublingual tablets are known under the trade namesSubutex® or Suboxone® both of which comprise the active agentbuprenorphine hydrochloride for drug substitution therapy.

The suitability of particularly buprenorphine for drug substitutiontherapy had been recognised early on in view of buprenorphine' s verylong elimination half-life (reported as approximately 20 to 37 hours),which allows a reduced frequency of administration. As a consequencedrug addicts who participate in drug substitution therapy have to reportless frequently to the medical agency or healthcare professionalsupervising the substitution programme.

Furthermore, the sublingual absorption of buprenorphine has theadvantage that an abuse by swallowing tablets of buprenorphine is lesslikely to occur. The tablets that are currently on the market in theform of Subutex® and Suboxone® preparations are both for sublingualadministration and typically disintegrate over a time period of five toten minutes. However, within that time period the drug addict may beable to divert the tablet before subsequently either selling the tabletson the street or isolating the active agents therefrom. In order toreduce of eliminate these problems, the present invention provides oralpharmaceutical dosage forms which comprise the active agentbuprenorphine and which release buprenorphine instantly after oral,preferably sublingual, administration of the drug.

It is understood that if reference is made in the context of thisinvention to the term “buprenorphine” this refers to the free base aswell as to any pharmaceutically acceptable salt thereof such as thehydrochloride, sulfate, bisulfate, tartrate, nitrate, citrate,bitartrate, phosphate, malate, maleate, hydrobromide, hydroiodide,fumarate, succinate salts and the like.

A particularly preferred pharmaceutically acceptable salt ofbuprenorphine is buprenorphine hydrochloride.

The provision of a pharmaceutical dosage form comprising buprenorphineor a pharmaceutically acceptable salt thereof in e.g. film-like orwafer-like shapes which allows for instant release of the active agentupon oral, preferably sublingual, administration of the dosage formshould prevent the type of abuse resulting from illicit diversion of thetablets by drug addicts participating in drug substitution therapyprogrammes.

In the context of the present invention instant release means thatsubstantially the whole amount of the buprenorphine or the respectivepharmaceutically acceptable salt thereof will be released in less thanfive minutes. Preferably, substantially all of the buprenorphine or itspharmaceutically acceptable salt thereof will be released within lessthan four, within less than three, within less than two and morepreferably within less than one minute.

In a particularly preferred embodiment, instant release refers to thesituation that substantially all of the buprenorphine or the respectivepharmaceutically acceptable salt thereof will be released within lessthan thirty seconds, within less than twenty seconds, or within lessthan ten seconds. In an even more preferred embodiment, the term“instant release” means that substantially all of the buprenorphine willbe released from the dosage form within less than five seconds or withinless than three seconds.

The term “substantially all” means that approximately 95% of the drugwill have been released.

The term “approximately” in the context of the present inventiondescribes a deviation from the indicated value of 10% and preferably of5%.

Such efficient release of the drug is hard to achieve with a sublingualtablet which generally requires a greater amount of time to melt or todisintegrate.

Fast-dissolving or rapidly disintegrating dosage forms for otherpharmaceutically active compounds are known which disintegrate withinseconds upon contact with the mucosal saliva of the mouth andparticularly the sublingual mucosa.

These pharmaceutical dosage forms and formulation principles are wellknown to the person skilled in the art and will be described in moredetail below.

As regards the dosage amount, the pharmaceutical compositions inaccordance with the present invention will typically comprise betweenapproximately 0.1 mg and approximately 16 mg of buprenorphine or apharmaceutically acceptable salt thereof such as buprenorphinehydrochloride. Preferred dosage amounts will be in the range of betweenapproximately 0.4 mg and approximately 12 mg or between approximately 2mg and approximately 8 mg buprenorphine or a pharmaceutically acceptablesalt thereof.

The oral pharmaceutical dosage forms in accordance with the inventionmay have the further characteristic of providing a C_(max) ofapproximately 1.5 to 2.5 ng/ml in the case of a dose of 4 mgbuprenorphine hydrochloride being administered. A preferred C_(max) inthe case of a dose of 4 mg of buprenorphine hydrochloride beingadministered may be approximately between 1.7 ng/ml to 2 ng/ml.

In the case of a dose of 8 mg buprenorphine hydrochloride beingadministered, the C_(max) may be approximately between 2.5 and 3.5ng/ml. In a preferred embodiment the C_(max) may be approximatelybetween 2.75 ng/ml and 3.25 ng/ml in the case of a dose of 8 mgbuprenorphine hydrochloride being administered.

In case of a dose of 16 mg buprenorphine hydrochloride beingadministered, the C_(max) may preferably be in the range ofapproximately 5 to 7 ng/ml. In a preferred embodiment the C_(max) may bebetween 5.5 and 6.5 ng/ml if 16 mg of buprenorphine hydrochloride areadministered.

The AUC₀₋₄₈ (i.e. the Area under the Curve for 48 hours afteradministration) may in the case of administration of 4 mg ofbuprenorphine hydrochloride be in the range of approximately 10 to 15hours×ng/ml. In a preferred embodiment the AUC₀₋₄₈ may be approximately12 to 13 hours×ng/ml. In the case of 8 mg buprenorphine hydrochloridebeing administered the AUC₀₋₄₈ may be approximately in the range of 15to 25 hours×ng/ml. In a preferred embodiment the AUC₀₋₄₈ in this casemay be between approximately 20 to 22 hours×ng/ml. In the case of 16 mgbuprenorphine hydrochloride being administered, the AUC₀₋₄₈ may be inthe range of 25 to 40 hours×ng/ml. In a preferred embodiment the AUC₀₋₄₈in this case may be in the range of approximately 30 to 35 hours×ng/ml.

The average T_(max) values for such preparations will preferably be fromapproximately 45 to approximately 90 minutes.

It is understood that the aforementioned pharmacokinetic parametersC_(max) and AUC₀₋₄₈ are average values that are obtained by measuringthe blood plasma levels in a group of eight to approximately twenty-fourpatients. These patients will be selected according to inclusion andexclusion criteria, as they are common for drug substitution programmes.It is understood that such patients typically will be of average weightand Caucasian origin.

The pharmaceutical dosage form in accordance with the invention will beadministered such that the maximal dosage per day is 32 mg ofbuprenorphine. Once a patient is enrolled in substitution therapy, theinitial dosage will be typically between 2 mg to 4 mg of buprenorphine.The formulations may be administered once a day, every two days,preferably every three days or even less frequently.

In a preferred embodiment, the oral dosage forms of the invention willadditionally comprise an opioid antagonist. Such antagonists may beselected from the group comprising naltrexone, naloxone, nalmefene,nalorphine, nalbuphine, naloxoneazinen, methylnaltrexone,ketylcyclazocine, norbinaltorphimine, naltrindol, 6-β-naloxol and6-β-naltrexol or the pharmaceutically acceptable salts thereof.

Especially preferred antagonists comprise naltrexone, nalmefene andnaloxone. Specifically preferred as an antagonist is naloxone and itshydrochloride salt.

It is understood, that if in the context of the present inventionreference is made to an opioid antagonist, this also not only refers tothe free base but also to pharmaceutically acceptable salts thereof suchas those mentioned for buprenorphine.

A particularly preferred antagonist is naloxone. Of the naloxone salts,naloxone hydrochloride dihydrate may be particularly preferable incombination with buprenorphine hydrochloride.

The pharmaceutical dosage forms in accordance with the invention willcomprise buprenorphine and the antagonist, which preferably is naloxone,in a weight ratio of from 1:1 to 10:1. A weight ratio of from 2:1 to 8:1may be preferred, with a weight ratio of 4:1 being particularlypreferred.

Thus, if an oral dosage form in accordance with the present inventionfor example comprises 2 mg buprenorphine hydrochloride it will compriseapproximately 0.5 mg naloxone. If the dosage form comprises 0.4 mgbuprenorphine hydrochloride, it will comprise 0.1 mg naloxone and if thedosage form comprises 8 mg buprenorphine hydrochloride it will comprisee.g. 2 mg naloxone hydrochloride.

A particularly preferred embodiment thus relates to an oral dosage formcomprising buprenorphine, preferably buprenorphine hydrochloride, andnaloxone, preferably naloxone hydrochloride, wherein the dosage formreleases said active agents within less than one minute, preferablywithin less than thirty seconds and more preferably within less than tenseconds after sublingual application of the dosage form. In addition,the dosage forms may provide the preferred values of the aforementionedpharmacokinetic parameters C_(max), and AUC₀₋₄₈.

Thus, the person skilled in the art will have to ensure that indeed anoral dosage form is used which is able to allow for incorporation ofsufficient amounts of buprenorphine and preferably also of naloxone andwhich at the same time disintegrates rapidly enough to release theactive agents instantly.

In one embodiment one may use non-gelatin film materials, e.g. films ofmodified cellulose materials as dosage forms. In this case,buprenorphine and optionally opioid antagonists such as naloxone areincorporated into the film matrix and films thus prepared may beadministered orally.

In accordance with this aspect of the invention, the active ingredientsmay be dissolved in a hydrophilic, organic system to form a homogenoussolution or dispersion. The solution or dispersion can then be appliedto one or more surfaces of a non-gelatin polymeric film, e.g. a drycellulose ether film, resulting in the active ingredient(s) and/orliquid carrier phase being transported through the surface of the “dry”film resulting in a new film composition.

The film substrate may remain completely intact or relatively physicallyunchanged immediately following the incorporation process. It can,however, be converted to any size or shape of unit dosage form.Alternatively, the film substrate may liquefy or dissolve partly orfully during the incorporation process, but nevertheless finally forminga single discrete film, after curing. Films according to this aspect ofthe invention are typically made up of one or more soluble polymer orpolymers which will otherwise degrade at the intended site of releaseafter administration in the mouth, e.g. sublingual administration, inorder to provide the instant release of the active agents. Suitablecellulose ether film bases include e.g. hydroxypropylmethylcellulose(HPMC), hydroxypropylcellulose (HPC), hydroxyethylmethylcellulose(HEMC), hydroxyethylcellulose (HEC), methylcellulose (MC),carboxymethylcellulose (CMC) and salts and derivates of all of theaforesaid materials. A particularly suitable cellulose ether for formingthe film is HPMC.

Optional ingredients may be added including colorants, emulsifiers,humectants, and anti-blocking agents.

Once one has a film being based on a cellulose ether available, in anext step the active ingredient(s) will be applied in the form of aliquid to the film. Appropriate means of liquid application onto thefilm substrate include extrusion, roller application, pouring, spraying,brush painting or whipping. Further details of the preparation of suchfilms can be taken e.g. from WO 2005/079750 A2 which is incorporated byreference herewith.

Another possible technology in order to provide the afore-describedpharmaceutical dosage forms of buprenorphine and preferably naloxone isdescribed in WO 03/030883. In this latter embodiment of the presentinvention, a thin film drug delivery composition includes (i) a flowablewater-soluble film-forming matrix and (ii) the active agent(s) uniformlystationed therein. Optionally a taste-masking agent may be coated orintimately associate with the active agent(s) to provide taste maskingof the active agent(s). The flowable water-soluble film-forming matrixtogether with the active agent(s) is formable into a dry film of lessthan about 380 microns in thickness, for example less than about 250microns in thickness.

The matrix may be a cellulosic material, a gum, a protein, a starch, aglucan and combinations thereof. For example one may use the alreadyaforementioned methylcellulose, HMC, HEC, HC, HPC, HPMC, HMPC, gumArabic, xanthan gum etc. The films are prepared according to standardtechnology and the active agents are displaced thereon and therein asdescribed in WO 03/030883.

Yet another interesting technology relates to immediate release drugdelivery forms as described in WO 99/17744, which is also incorporatedby reference herein as far as it describes fast releasing oral dosageforms. The person skilled in the art will understand that the processesand dosage forms in WO 99/17744 may be used to obtain the aforementioneddescribed pharmaceutical dosage forms of buprenorphine and preferablyalso naloxone.

One may of course also use fast disintegrating tablets that disintegrateupon contacting the saliva, e.g. under the tongue, following oraladministration. Such fast-disintegrating tablets are described e.g. inWO 99/44580 and are well known to the person skilled in the art.

A particularly interesting technology for fast-releasing dosage formsthat may be used for the purpose of the present invention to provide anoral dosage form of buprenorphine and preferably an opioid antagonistsuch as naloxone can be taken from WO 96/26720.

Therein it is described how the active agent selegiline is formulatedinto a rapidly releasing dosage form that can be used e.g. forsublingual administration. WO 96/26720 describes in detail a“fast-dispersing dosage form” with the term encompassing all types ofdosage forms being described in U.S. Pat. No. 5,120,549, U.S. Pat. No.5,079,018, WO 93/12769, U.S. Pat. No. 5,298,261 and WO 91/04757.

As for WO 96/26720 in the case of the active agent selegiline, thepresent invention contemplates particularly using fast-dispersing dosageforms as described in UK patent number 1548022, that is, a solidfast-dispersing dosage form comprising a network of the activeingredient(s) and a water-soluble or water-dispersible carrier which isinert towards the active ingredient, the network having been obtained bysubliming solvent from a composition in the solid state, thatcomposition comprising the active ingredient and a solution of thecarrier in a solvent.

It is preferred that such a composition in accordance with the inventiondisintegrates within one to ten seconds, and particularly within two toeight seconds of being placed in the oral cavity and particularlysublingually.

The composition will preferably contain in addition to the activeingredient, matrix forming agents and secondary components.

Matrix forming agents suitable for use in this aspect of the presentinvention include materials derived from animal or vegetable proteins,such as gelatins, dextrins and soy, wheat and psyllium seed proteins,gums such as acacia, guar, agar, and xanthan, polysaccharides,alginates, carboxymethylcelluloses, carrageenans, dextrans, pectins,synthetic polymers such as polyvinylpyrrolidone, and polypeptide/proteinor polysaccharide complexes such as gelatin-acacia complexes.

Other matrix forming agents suitable for use in the present inventioninclude sugars such as mannitol, dextrose, lactose, galactose andtrehalose; cyclic sugars such as cyclodextrin; inorganic salts such assodium phosphate, sodium chloride and aluminium silicates; and aminoacids having from 2 to 12 carbon atoms such as a glycine, L-alanine,L-aspartic acid, L-glutamic acid, L-hydroxyproline, L-isoleucine,L-leucine and L-phenylalanine.

One or more matrix forming agents may be incorporated into the solutionor suspension prior to solidification. The matrix forming agent may bepresent in addition to a surfactant or to the exclusion of a surfactant.In addition to forming the matrix, the matrix forming agent may aid inmaintaining the dispersion of any active ingredient within the solutionor suspension.

Secondary components such as preservatives, antioxidants, surfactants,viscosity enhancers, colouring agents, flavouring agents, pH modifiers,sweeteners or taste-masking agents may also be incorporated into thecomposition. Suitable colouring agents include red, black and yellowiron oxides. Suitable flavouring agents include mint, raspberry,liquorice, orange, lemon, grapefruit, caramel, vanilla, cherry and grapeflavours and combinations of these. Suitable pH modifiers include citricacid, tartaric acid, phosphoric acid, hydrochloric acid and maleic acid.Suitable sweeteners include aspartame and thaumatin. Suitable taste-masking agents include sodium bicarbonate, ion-exchange resins,cyclodextrin inclusion compounds, adsorbates or microencapsulatedactives.

Such fast-dispersing dosage forms containing buprenorphine andpreferably an opioid antagonist such as naloxone may be similarlyobtained as described in GB 1548022B or WO 96/26720, in particularExample 1 of the latter, which are incorporated herein in theirentirety.

A particularly preferred embodiment of the present invention relates todosage forms, which are produced along the lines described in WO03/070227 A1.

This prior art reference describes taste- masked, film- type orwafer-type medicinal preparations. It is to be understood that thedosage forms in accordance with the present invention may preferably besuch film- type or wafer-type medicinal preparations with the taste-masking being only an optional feature.

Flat active agent carriers that have a film- type or wafer-typestructure provide for various advantages. As a consequence of the lowthickness in comparison to the surface area, there is only a shortdiffusion pathway if such a dosage form is applied e.g. to the mucosa ofthe oral cavity. This typically leads to a very rapid release of theactive agents which can then be quickly, efficiently and directlyabsorbed by the mucosa of the oral cavity and particularly sublinguallyif the active agent is absorbable at all via that route. Thus, in caseof buprenorphine such very flat film-type or wafer-type dosage forms arehighly desirable as they will allow for the provision of an instantrelease of active ingredient, thereby minimising the abuse problemsencountered with the formulations of the prior art.

Flat active agent carriers have been developed for different purposes.One of the basic prior art references in this context is DE 27 46 414 inwhich active agent, binding agent and additional excipients areprocessed to yield a dosage form in the form of film- type strand.

One of the advantages of wafer-type pharmaceutical dosage forms asdescribed in WO 03/070227 A1 is that there is a direct correlationbetween the amount of the active agent and the length of a certain partof the strand in view of the homogenous thickness, density and width.Thus, one can easily obtain a certain unit dosage by simply cutting thewafer-like dosage form in to appropriately sized pieces.

Such film-type or wafer-type dosage forms in accordance with the presentinvention are characterised in that they comprise a matrix which isformed from at least one matrix-forming polymer and in whichbuprenorphine and preferably an opioid antagonist such as naloxone aredissolved or homogenously dispersed.

The rapidly disintegrating matrix of the pharmaceutical dosage forms inaccordance with the invention comprises as one of its basic substanceswater-soluble polymers or mixtures of such polymers. Preferablysynthetic or partially synthetic polymers or naturally occurringbiopolymers are used which can form films and are water-soluble.Particularly suitable for this purpose are polymers which may beselected from the group comprising cellulose derivatives,polyvinylalcohol, polyacrylates and polyvinylpyrrlidone.

Within the cellulose derivatives, hydroxypropylmethylcellulose,carboxymethylcellulose, sodium carboxymethylcellulo se,hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose, andhydroxypropylmethylcellulose may be used. One may also use water-solublepolysaccharides being derived from plants or microbes. Preferredpolysaccharides include pullulan, trantan, alginate, dextrin andpectins.

One may also use proteins and preferably gelatin or other gel-formingproteins. One may also use starch and starch derivatives, gelatin,polyvinylpyrrilidone, gum Arabic, pullulan, acrylates, polyethyleneoxide with a particular focus on polyox 10, polyox 80, polyox 205,polyox 301, polyox 750 or copolymers of methylvinylether and maleic acidanhydride.

The person skilled in the art will appreciate that the extent to whichbuprenorphine and optionally an opioid antagonist such as naloxone areinstantly released depends in part on the type of matrix-forming polymerchosen. For example, a dosage form using polyvinylalcohol asmatrix-forming polymer may disintegrate faster than a dosage form usingHPMC as matrix-forming polymer. The disintegration time may be adjustedby mixing a combination of different polymers in suitable amounts.

The person skilled in the art also knows disintegrating agents, whichcan “pull” water into the matrix which then pushes the dosage formsapart. Thus, such disintegrating agents may also be used for adjustmentof the disintegration time.

In order to allow absorption of buprenorphine over the mucosa of themouth, and particularly sublingually, in one embodiment the dosage formsmay additionally use agents that enhance absorption of the active agent,i.e. so-called permeation enhancers.

Such permeation enhancers may be selected from the group comprisingpropandiol, dexpanthenol, and oleic acid. The permeation enhancers mayalso be selected from the group comprising saturated or unsaturatedfatty acids, hydrocarbons, linear or branched fatty alcohols,dimethylsulfoxide, propylene glycol, decanol, dodecanol,2-octyldodecanol, glycerine, ethanol or other alcohols.

According to a preferred embodiment the film-type or wafer-type oraldosage forms of the present invention in the presence of saliva candisintegrate within e.g. one second to three minutes or within fiveseconds to one minute or five seconds to thirty seconds.

The disintegration times of the oral dosage forms in accordance with theinvention are measured according to the European pharmacopoeia, 4^(th)edition 2002.

In the present case where the active agent buprenorphine is administeredsublingually, the dosage forms in accordance with the invention mayadditionally comprise an excipient that mediates adhesion to therespective mucosa. Examples of such muco-adhesive substances are e.g.polyacrylic acid, carboxymethylcellulose, hydroxymethylcellulose,methylcellulose, alginic acid, gelatin and gum Arabic.

The thickness of the film-type or wafer-type dosage forms in accordancewith the invention may typically be between 5 μm and 10 mm, 30 μm and 2mm, or 0.1 mm and 1 mm. The dosage forms may be round, oval, elliptic,or may have a triangular, quadrangular, or multi-angular form. Typicallythe surface of the pharmaceutical dosage forms in accordance with theinvention is flat.

As stated above, the film-type or wafer-type matrix of the dosage formsof this aspect of the invention comprises at least one matrix-formingpolymer. The matrix-forming polymer(s) are an essential component of thematrix.

The polymer amount within the matrix may be between approximately 3% byweight and approximately 98% by weight and preferably between 7 and 80%by weight and even more preferably between 20 and 50% by weight, theweight percentages being based on the total weight of the dosage forms.

The mucoadhesive properties as well as the disintegrating properties areto a large extent determined by the type of matrix-forming polymer(s),as well as the relative amount of the polymer(s) used in the dosageforms.

Besides the matrix-forming polymers, buprenorphine and optionally anopioid antagonist, further excipients may be present within the matrix.

These additional excipients may be filling agents such as SiO₂,colorants and pigments (such as TiO₂) disintegrating agents particularlythose which attract water (such Aerosil), emulsifying agents,plasticizers, sweeteners or conserving agents. Additionally, auxiliaryexcipients such as stabilising agents or antioxidants may be added.

If a taste-masking effect is to be obtained, the dosage form inaccordance with this aspect of the invention may comprise additionally acarbon dioxide-forming agent that upon contact with the saliva developscarbon dioxide. Such carbonates are well known in the prior art fromeffervescent formulations and include e.g. sodium hydrogen carbonate,sodium carbonate, potassium hydrogen carbonate or potassium carbonate.In order to enhance CO₂ development, one may add acidic components suchas e.g. sodium dihydrogen- or disodiumhydrogen phosphate, sodiumtatrate, sodium ascorbate etc. One may of course also use citric acid,tartartic acid, adipinic acid, ascorbic acid, acetic acid, lactic acidetc.

Thus, one preferred embodiment of the invention relates to oral dosageforms of film-type or wafer-type film as described above which comprisebuprenophine and optionally an opioid antagonist such as naloxone withthe oral dosage form having the above-described characteristics as tothe amount of buprenophine and the optional antagonist, thepharmacokinetic parameters C_(max) and AUC₀₋₄₈ and the instant releaseof the active agents from the dosage form. The person skilled in the artwill know how to produce such film-type or wafer-type dosage forms onthe basis of the above-mentioned information. This may be achieved bycommon film-coating technologies, extrusion processes, spray drying etc.More details can be taken from WO 03/070227.

The person skilled in the art will also know other dosage forms, whichallow an instant release of the active agent upon sublingualadministration, so that such formulation technology may be applied tobuprenorphine and optionally opioid antagonists preferably beingnaloxone.

In a further embodiment, the present invention relates to the use of anyof the aforementioned described pharmaceutical dosage forms comprisingbuprenorphine and optionally an opioid antagonist being preferablynaloxone for the manufacture of a medicament for drug substitutiontherapy. The pharmaceutical dosage forms described above may, of course,also be used in the manufacture of a medicament for treating pain. Thus,the dosage forms may be used in opioid naïve patients or patients whoare not dependent on opioids in order to provide fast pain relief byoral, preferably sublingual, administration of the preparations.

As far as drug substitution therapy is concerned, the effectiveness ofthe afore-described amounts and pharmacokinetic parameters ofbuprenorphine and optionally naloxone are known from the pharmaceuticalpreparations Subutex® and Suboxone®. Therefore it can be firmly assumedthat the same efficacy will be observed in drug substitution therapywith the inventive preparations of the present invention.

One of the advantages of the preparations in accordance with the presentinvention is to be seen in the fact that in view of the instant releaseof buprenorphine, a drug addict will have a diminished chance ofillicitly diverting the dosage form given that particularly thefilm-type and the wafer-type of dosage forms will disintegrate instantlyupon contact with the saliva during sublingual administration. If anopioid antagonist such as naloxone is included in the dosage form it isadditionally ensured that parenteral abuse of such dosage forms bydissolving the active agents out of the rapidly disintegrating dosageforms will be significantly diminished.

In yet a further embodiment, the present invention relates to a methodof drug substitution therapy in drug addicts by administering apharmaceutical formulation as described above which instantly releasesbuprenorphine and optionally an opioid antagonist being preferablynaloxone upon oral, preferably sublingual, administration to a patient.

One embodiment of the present invention also relates to a method oftreating pain by administering a pharmaceutical formulation as describedabove which instantly releases buprenorphine and optionally an opioidantagonist being preferably naloxone upon oral, preferably sublingual,administration to a patient.

The present invention has been described by reference to some of itspreferred embodiments. This description is, however, in no way meant tolimit the scope of the invention. Other embodiments that do not departfrom the spirit of the invention should be similarly encompassed andaddressed by the aforementioned description and the subsequent claims.

What is claimed:
 1. A method for treating pain, the method comprisingcontacting the sublingual mucosa of a patient in need thereof with asublingual film dosage form comprising: a) approximately 0.1 mg toapproximately 16 mg buprenorphine, or an equivalent amount of apharmaceutically acceptable salt thereof; b) naloxone or apharmaceutically acceptable salt thereof; and c) at least onenon-gelatin polymeric film-forming material in which the buprenorphineor the equivalent amount of the pharmaceutically acceptable salt thereofand the naloxone or the pharmaceutically acceptable salt thereof, aredissolved or homogeneously dispersed; the buprenorphine or theequivalent amount of the pharmaceutically acceptable salt thereof andthe naloxone or the pharmaceutically acceptable salt thereof beingpresent in the sublingual film dosage form in a weight ratio of from 1:1to 10:1; such that within less than 5 minutes after contacting thesublingual mucosa of the patient with the sublingual film dosage form,the buprenorphine or the pharmaceutically acceptable salt thereof andapproximately substantially all of the naloxone or the pharmaceuticallyacceptable salt thereof contact the sublingual mucosa, and wherein saidcontacting achieves: (i) an average buprenorphine AUC₀₋₄₈ fromapproximately 10 to approximately 15 (hrs*ng)/ml when the sublingualfilm dosage form includes 4 mg buprenorphine or an equivalent amount ofa pharmaceutically acceptable salt thereof, (ii) an averagebuprenorphine AUC₀₋₄₈ from approximately 15 to approximately 25(hrs*ng)/ml when the sublingual film dosage form includes 8 mgbuprenorphine or an equivalent amount of a pharmaceutically acceptablesalt thereof, or (iii) an average buprenorphine AUC₀₋₄₈ fromapproximately 25 to approximately 40 (hrs*ng)/ml when the sublingualfilm dosage form includes 16 mg buprenorphine or an equivalent amount ofa pharmaceutically acceptable salt thereof.
 2. The method of claim 1,wherein said contacting achieves: (i) an average buprenorphine C_(max)from approximately 1.5 ng/ml to approximately 2.25 ng/ml when thesublingual film dosage form includes 4 mg buprenorphine or an equivalentamount of a pharmaceutically acceptable salt thereof, (ii) an averagebuprenorphine C_(max) from approximately 2.5 ng/ml to approximately 3.5ng/ml when the sublingual film dosage form includes 8 mg buprenorphineor an equivalent amount of a pharmaceutically acceptable salt thereof,or (iii) an average buprenorphine C_(max) from approximately 5.5 ng/mlto approximately 6.5 ng/ml when the sublingual film dosage form includes16 mg buprenorphine or an equivalent amount of a pharmaceuticallyacceptable salt thereof.
 3. The method of claim 1, wherein thesublingual film dosage form comprises approximately 2 mg toapproximately 8 mg buprenorphine or the equivalent amounts of apharmaceutically salt thereof.
 4. The method of claim 1, wherein thesublingual film dosage form comprises buprenorphine or the equivalentamount of the pharmaceutically acceptable salt thereof and naloxone or apharmaceutically acceptable salt thereof in a weight ratio of 2:1 to8:1.
 5. The method of claim 4, wherein the sublingual film dosage formcomprises buprenorphine or the equivalent amount of the pharmaceuticallyacceptable salt thereof and naloxone or the pharmaceutically acceptablesalt thereof in a weight ratio of 4:1.
 6. The method of claim 1, whereinthe sublingual film dosage form provides an average T_(max) fromapproximately 45 to approximately 90 minutes after administration. 7.The method of claim 1, wherein the sublingual film dosage form comprisesthe equivalent amount of buprenorphine hydrochloride.
 8. The method ofclaim 1, wherein said contacting achieves an average buprenorphineAUC₀₋₄₈ from approximately 10 to approximately 15 (hrs*ng)/ml when thesublingual film dosage form comprises 4 mg buprenorphine or anequivalent amount of a pharmaceutically acceptable salt thereof.
 9. Themethod of claim 1, wherein said contacting achieves an averagebuprenorphine AUC₀₋₄₈ from approximately 15 to approximately 25(hrs*ng)/ml when the sublingual film dosage form comprises 8 mgbuprenorphine or an equivalent amount of a pharmaceutically acceptablesalt thereof.
 10. The method of claim 1, wherein said contactingachieves an average buprenorphine C_(max) from approximately 1.5 ng/mlto approximately 2.25 ng/ml when the sublingual film dosage formcomprises 4 mg buprenorphine or an equivalent amount of apharmaceutically acceptable salt thereof.
 11. The method of claim 1,wherein said contacting achieves an average buprenorphine C_(max) fromapproximately 2.5 ng/ml to approximately 3.5 ng/ml when the sublingualfilm dosage form comprises 8 mg buprenorphine or an equivalent amount ofa pharmaceutically acceptable salt thereof.
 12. The method of claim 1,wherein the sublingual film dosage form further comprises a pH modifier.13. The method of claim 12, wherein the pH modifier is selected from thegroup consisting of citric acid, tartaric acid, phosphoric acid,hydrochloric acid, and maleic acid.
 14. The method of claim 1, whereinthe sublingual film pharmaceutical dosage form is mucoadhesive.
 15. Themethod of claim 1, wherein the non-gelatin polymeric film-formingmaterial is a modified cellulose material.
 16. The method of claim 15,wherein the modified cellulose material is a cellulose ether.
 17. Themethod of claim 16, wherein the cellulose ether is selected from thegroup consisting of hydroxypropylmethylcellulose (HPMC),hydroxypropylcellulose (HPC), hydroxyethylmethylcellulose (HEMC),hydroxyethylcellulose (HEC), methylcellulose (MC), andcarboxymethylcellulose (CMC).
 18. The method of claim 17, wherein thecellulose ether is HPMC.
 19. A method of treating pain, the methodcomprising contacting the sublingual mucosa of a patient in need thereofwith a sublingual film dosage form comprising: a) an amount ofbuprenorphine, or an equivalent amount of a pharmaceutically acceptablesalt thereof, sufficient to provide an average buprenorphine C_(max) ofless than about 7 ng/ml and an average buprenorphine AUC₀₋₄₈ of lessthan 40 (hrs*ng)/ml; b) naloxone or a pharmaceutically acceptable saltthereof; and c) at least one non-gelatin polymeric film-forming materialin which the buprenorphine or the equivalent amount of thepharmaceutically acceptable salt thereof and the naloxone or thepharmaceutically acceptable salt thereof, are dissolved or homogeneouslydispersed; the buprenorphine or the equivalent amount of thepharmaceutically acceptable salt thereof and the naloxone or thepharmaceutically acceptable salt thereof being present in the sublingualfilm dosage form in a weight ratio of from 1:1 to 10:1; such that withinless than 5 minutes after contacting the sublingual mucosa of thepatient with the sublingual film dosage form, the buprenorphine or thepharmaceutically acceptable salt thereof and approximately substantiallyall of the naloxone or the pharmaceutically acceptable salt thereofcontact the sublingual mucosa.
 20. The method of claim 19, wherein theamount of buprenorphine is 2 mg, 4 mg, 8 mg, or 16 mg.
 21. The method ofclaim 19, wherein the weight ratio is 2:1 to 8:1.
 22. The method ofclaim 21, wherein the weight ratio is 4:1.
 23. The method of claim 19,wherein the non-gelatin polymeric film-forming material is a modifiedcellulose material.
 24. The method of claim 23, wherein the modifiedcellulose material is hydroxypropylmethylcellulose.